Reversible cystogenesis in juvenile primate ADPKD models: evidence from PKD1 heterozygous monkeys.

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder caused predominantly by heterozygous mutations in the PKD1 gene, leading to progressive renal cyst formation. While PKD1 mutant mouse models have provided mechanistic insights, PKD1 heterozygous mice fail to replicate the early cystogenesis observed in human patients. To address this gap, we conducted a longitudinal study using PKD1 heterozygous cynomolgus monkeys. Serial renal ultrasonography from birth to five years of age-corresponding to human childhood-revealed progressive cyst development. Remarkably, a subset of cysts, particularly smaller ones, exhibited spontaneous regression over time. This phenomenon was also observed in PKD1 mosaic monkeys harboring mixed variant patterns. In contrast, monkeys with biallelic PKD1 loss-of-function variants developed severe cystic disease, kidney enlargement, hepatic cysts, and elevated serum creatinine, resembling the clinical features of advanced ADPKD. These findings demonstrate that early renal cysts may possess intrinsic plasticity, challenging the conventional view of ADPKD as a relentlessly progressive disorder. Our results suggest that the early stages of cystogenesis represent a potential therapeutic window for intervention, in which cyst regression may be promoted. The PKD1 heterozygous monkey model thus provides a valuable platform for studying the developmental dynamics of ADPKD and for evaluating novel therapeutic approaches targeting early cystic changes.